Monitoring DAT in Live Mice Abstract Expressed exclusively in dopaminergic neurons, the dopamine transporter gene (DAT/SLC6A3) is a risk factor for many diseases including drug abuse, depression and bipolar disorder, based on hundreds of association studies. Since DNA sequence variation in the human DAT is correlated with striatal DAT protein levels in humans, it is postulated that altered DAT activity confers the risk. However, it is not known whether or not altered DAT activity is indeed correlated with abnormal behaviors or diseases. To fill in this critical knowledge gap, here we propose to develop a mouse line where DAT carries a reporter gene that encodes a secreted Gaussia luciferase (GLuc) with desired reporter qualities such as short in vivo half-life, high sensitivity and large dynamic range. This DAT-GLuc line will allow monitoring DAT activity sequentially in the same live mice under various environments including drugs of abuse, simply by measuring GLuc activity in the circulated fluid. DAT-GLuc aims to follow the DAT activity and correlate the activity with behaviors or efficacy of DAT-related medications in mice. This gene activity-reporting mouse line will complement the current in vivo technologies including brain imaging (for proteins) and microdialysis (for small molecules). PUBLIC HEALTH RELEVANCE: Monitoring DAT in live mice Project Narrative This research will generate a mouse line that uses luciferase to report the activity of the dopamine transporter gene (DAT), whose human orthologue is a risk factor for more than ten neuropsychiatric diseases. This DAT-reporting line will provide the research community a new tool to model and treat DAT-related diseases.